Tygacil prescribing information pdf

Additives should not be introduced into this solution. Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product.

Discard unused portion. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of ZYVOX I. Injection and with any other drug s administered via this common line. Compatible intravenous solutions include 0. Injection was combined with the following drugs during simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole.

Injection was combined with ceftriaxone sodium. Gently tap bottle to loosen powder. Add a total of mL distilled water in two portions.

After adding the first half, shake vigorously to wet all of the powder. Then add the second half of the water and shake vigorously to obtain a uniform suspension. After constitution, each 5 mL of the suspension contains mg of linezolid. Before using, gently mix by inverting the bottle 3 to 5 times. Do not shake. Store constituted suspension at room temperature. Use within 21 days after constitution. When constituted as directed, each bottle will contain mL of a suspension providing the equivalent of mg of linezolid per each 5 mL.

ZYVOX formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components. Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B e. Myelosuppression including anemia, leukopenia, pancytopenia, and thrombocytopenia has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels.

Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibacterial drug therapy.

Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression. Peripheral and optic neuropathies have been reported in patients treated with ZYVOX, primarily in those patients treated for longer than the maximum recommended duration of 28 days.

In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Peripheral and optic neuropathy has also been reported in children. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended.

If peripheral or optic neuropathy occurs, the continued use of ZYVOX in these patients should be weighed against the potential risks. Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration of ZYVOX and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors SSRIs , have been reported.

In some cases, a patient already receiving a serotonergic antidepressant or buspirone may require urgent treatment with linezolid. If alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered. The patient should be monitored for two weeks five weeks if fluoxetine was taken or until 24 hours after the last dose of linezolid, whichever comes first.

Symptoms of serotonin syndrome or NMS-like reactions include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that include extreme agitation progressing to delirium and coma. The patient should also be monitored for discontinuation symptoms of the antidepressant see package insert of the specified agent s for a description of the associated discontinuation symptoms. While causality has not been established, this observed imbalance occurred primarily in linezolid-treated patients in whom either Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline, but was not seen in patients with Gram-positive infections only.

Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections. Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections.

It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [ see Indications and Usage 1 ].

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. Hypertoxin producing strains of C. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving ZYVOX should receive immediate medical evaluation. Convulsions have been reported in patients when treated with linezolid.

In some of these cases, a history of seizures or risk factors for seizures was reported. Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, a reversible, nonselective MAO inhibitor.

Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be cautioned of potential hypoglycemic reactions when treated with linezolid. If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or linezolid may be required.

In reported cases, the signs and symptoms included confusion, somnolence, generalized weakness, and in severe cases led to respiratory failure and even death. Phenylalanine can be harmful to patients with phenylketonuria PKU. Prescribing ZYVOX in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ZYVOX formulations was evaluated in 2, adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days. Of the patients treated for uncomplicated skin and skin structure infections uSSSIs , For all other indications, Of the patients treated for uSSSIs, 3. For all other indications, discontinuations due to drug-related adverse events occurred in 2. The most common reported drug-related adverse events leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting.

The safety of ZYVOX formulations was evaluated in pediatric patients ranging in age from birth through 11 years, and in pediatric patients aged 5 through 17 years of these were age 5 through 11 and were age 12 to These patients were enrolled in two Phase 3 comparator-controlled clinical trials and were treated for up to 28 days. In the study of hospitalized pediatric patients birth through 11 years with Gram-positive infections, who were randomized 2 to 1 linezolid: vancomycin , mortality was 6.

However, given the severe underlying illness in the patient population, no causality could be established. Of the pediatric patients treated for uSSSIs, Of the pediatric patients treated for uSSSIs, 1. For all other indications, discontinuations due to drug-related adverse events occurred in 0.

ZYVOX has been associated with thrombocytopenia when used in doses up to and including mg every 12 hours for up to 28 days. Thrombocytopenia associated with the use of ZYVOX appears to be dependent on duration of therapy generally greater than 2 weeks of treatment. No related clinical adverse events were identified in Phase 3 clinical trials in patients developing thrombocytopenia.

Bleeding events were identified in thrombocytopenic patients in a compassionate use program for ZYVOX; the role of linezolid in these events cannot be determined [ see Warnings and Precautions 5. Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between ZYVOX and the comparators.

These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of adult and pediatric patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 4, 5, 6, and 7. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:.

Linezolid is a reversible, nonselective inhibitor of monoamine oxidase [ see Contraindications 4. Linezolid has the potential for interaction with adrenergic and serotonergic agents [ see Warnings and Precautions 5. Available data from published and postmarketing case reports with linezolid use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. When administered during organogenesis, linezolid did not cause malformations in mice, rats, or rabbits at maternal exposure levels approximately 6.

However, embryo-fetal lethality was observed in mice at 6. When female rats were dosed during organogenesis through lactation, postnatal survival of pups was decreased at doses approximately equivalent to the estimated human exposure based on AUCs see Data.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U. In mice, embryo-fetal toxicities were observed only at doses that caused maternal toxicity clinical signs and reduced body weight gain. Fetal malformations were not observed.

The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.

Linezolid is present in breast milk. There is no information on the effects of linezolid on the breastfed infant; however, diarrhea and vomiting were the most common adverse reactions reported in clinical trials in infants receiving linezolid therapeutically [ see Adverse Reactions 6.

There is no information on the effects of linezolid on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for linezolid and any potential adverse effects on the breastfed child from linezolid or from the underlying maternal condition. The safety and effectiveness of ZYVOX for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years [ see Indications and Usage 1 , Clinical Pharmacology The safety and effectiveness of ZYVOX for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years [ see Clinical Studies 14 ]:.

Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid CSF linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.

The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure AUC compared with adults. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. The chemical name for linezolid is S -N-[[3-[3-Fluoro 4-morpholinyl phenyl]oxooxazolidinyl] methyl]-acetamide. Its molecular weight is Injection is supplied as a ready-to-use sterile isotonic solution for intravenous infusion.

Each mL contains 2 mg of linezolid. Inactive ingredients are dextrose monohydrate Inactive ingredients are carnauba wax, corn starch, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.

Following constitution, each 5 mL contains mg of linezolid. Inactive ingredients are aspartame, citric acid, colloidal silicon dioxide, flavors, mannitol, microcrystalline cellulose and carboxymethylcellulose sodium, sodium benzoate, sodium chloride, sodium citrate, sucrose, and xanthan gum [ see Patient Counseling Information 17 ].

At both the mg and 1, mg ZYVOX doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time. The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8. Plasma concentrations of linezolid at steady-state after oral doses of mg given every 12 hours are shown in Figure 1.

Figure 1. Linezolid is extensively absorbed after oral dosing. Therefore, linezolid may be given orally or intravenously without dose adjustment. Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1. Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well-perfused tissues.

The proposed pediatric doses of TYGACIL were chosen based on exposures observed in pharmacokinetic trials, which included small numbers of pediatric patients [see Use in Specific Populations 8. There are no data to provide dosing recommendations in pediatric patients with hepatic impairment. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug. The vial should be gently swirled until the drug dissolves.

Reconstituted solution must be transferred and further diluted for intravenous infusion. Withdraw 5 mL of the reconstituted solution from the vial and add to a mL intravenous bag for infusion for a mg dose, reconstitute two vials; for a 50 mg dose, reconstitute one vial. The reconstituted solution should be yellow to orange in color; if not, the solution should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration e.

If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of TYGACIL with 0. Injection should be made with an infusion solution compatible with tigecycline and with any other drug s administered via this common line. Compatible intravenous solutions include 0. For Injection: Each single-dose 10 mL glass vial contain 50 mg of tigecycline as an orange lyophilized powder for reconstitution.

Reactions have included anaphylactic reactions [see Warnings and Precautions 5. An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in TYGACIL-treated patients versus comparator-treated patients.

In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4. In a pooled analysis of these trials, based on a random effects model by trial weight, the adjusted risk difference of all-cause mortality was 0. The adjusted risk difference for mortality stratified by trial weight was 0.

The cause of this mortality difference has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. In addition, patients were allowed to receive specified adjunctive therapies. TYGACIL is structurally similar to tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-class antibacterial drugs.

Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Hepatic dysfunction may occur after the drug has been discontinued. Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment.

The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis.

Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis [see Adverse Reactions 6. The use of TYGACIL during tooth development last half of pregnancy, infancy, and childhood to the age of 8 years may cause permanent discoloration of the teeth yellow-gray-brown.

This adverse reaction is more common during long-term use of tetracyclines, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. The use of TYGACIL during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue.

This reaction was shown to be reversible when the tetracycline was discontinued. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. Hypertoxin producing strains of C. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. Monotherapy with tigecycline should be avoided in patients with complicated intra-abdominal infections cIAI secondary to clinically apparent intestinal perforation. Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.

Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia.

Prescribing TYGACIL in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.

The cause of the imbalance has not been established. Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see Warnings and Precautions 5. The most common adverse reactions were nausea and vomiting which generally occurred during the first 1 — 2 days of therapy. Body as a Whole : injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis.

Hemic and Lymphatic System : prolonged activated partial thromboplastin time aPTT , prolonged prothrombin time PT , eosinophilia, increased international normalized ratio INR , thrombocytopenia.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Concomitant use of TYGACIL and calcineurin inhibitors such as tacrolimus or cyclosporine may lead to an increase in serum trough concentrations of the calcineurin inhibitors. Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.

TYGACIL, like other tetracycline class antibacterial drugs, may cause permanent discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy [see Warnings and Precautions 5. Administration of intravenous tigecycline in pregnant rats and rabbits during the period of organogenesis was associated with reduction in fetal weights and an increased incidence of skeletal anomalies delays in bone ossification at exposures of 5 and 1 times the human exposure at the recommended clinical dose in rats and rabbits, respectively.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U. The use of tetracycline-class antibacterial drugs, that includes TYGACIL, during tooth development second and third trimester of pregnancy may cause permanent discoloration of deciduous teeth. This adverse reaction is more common during long-term use of tetracyclines but has been observed following repeated short-term courses.

TYGACIL may cause reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy.

In preclinical safety studies, 14 C-labeled tigecycline crossed the placenta and was found in fetal tissues. There are no data on the presence of tigecycline in human milk; however, tetracycline-class antibacterial drugs are present in breast milk. It is not known whether tigecycline has an effect on the breastfed infant or on milk production. Tigecycline has low oral bioavailability; therefore, infant exposure is expected to be low. Tigecycline is present in rat milk with little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.

When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the theoretical risk of dental discoloration and inhibition of bone growth, avoid breastfeeding if taking TYGACIL for longer than three weeks. A lactating woman may also consider interrupting breastfeeding and pumping and discarding breastmilk during administration of TYGACIL and for 9 days approximately 5 half-lives after the last dose in order to minimize drug exposure to a breastfed infant.

Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. In situations where there are no other alternative antibacterial drugs, dosing has been proposed for pediatric patients 8 to 17 years of age based on data from pediatric pharmacokinetic studies [see Dosage and Administration 2. Because of effects on tooth development, use in patients under 8 years of age is not recommended [see Warnings and Precautions 5.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.

No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single mg dose of tigecycline [see Clinical Pharmacology In patients with severe hepatic impairment Child Pugh C , the initial dose of tigecycline should be mg followed by a reduced maintenance dose of 25 mg every 12 hours. No specific information is available on the treatment of overdosage with tigecycline. In children above eight years of age, treatment is only given after consulting with a doctor with appropriate experience in the management of infectious diseases, and should be given as an infusion over a period of 60 minutes.

In children from 8 to 12 years old a dose of 1. Treatment lasts from 5 to 14 days. In children from 12 to 18 years a dose of 50 mg is given every 12 hours for a period of 5 to 14 days.

By blocking the production of new proteins, the bacteria cannot multiply and they eventually die. The list of bacteria against which Tygacil is active can be found in the summary of product characteristics also part of the EPAR.

Tygacil has been compared with other antibiotics in four main studies. In two of these studies, Tygacil was compared with the combination of vancomycin and aztreonam in 1, patients with complicated skin and soft tissue infections not including infected diabetic foot ulcers.

An additional study compared Tygacil with the antibiotic ertapenem in diabetic patients with moderate to severe foot infections. In all of the studies, the main measure of effectiveness was the number of patients whose infection was cured.

In the four main studies, Tygacil was as effective as the comparator antibiotics. Although there are few data in children, studies suggest that Tygacil can be a treatment alternative for complicated skin and soft tissue or abdominal infections, with bacteria resistant to other antibiotics.

For the full list of all side effects reported with Tygacil, see the package leaflet. Tygacil must not be used in people who are hypersensitive allergic to tigecycline or any of the other ingredients.

Patients allergic to tetracycline antibiotics may also be allergic to Tygacil. A risk management plan has been developed to ensure that Tygacil is used as safely and effectively as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Tygacil, including the appropriate precautions to be followed by healthcare professionals and patients.

The European Commission granted a marketing authorisation valid throughout the European Union for Tygacil on 24 April For more information about treatment with Tygacil, read the package leaflet also part of the EPAR or contact your doctor or pharmacist.

More detail is available in the summary of product characteristics.